rs200773268

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_033629.6(TREX1):c.290G>A(p.Arg97His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,611,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 1 hom. )

Consequence

TREX1
NM_033629.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 3.42

Variant links:

Genes affected

TREX1 (HGNC:12269): (three prime repair exonuclease 1) This gene encodes a nuclear protein with 3' exonuclease activity. The encoded protein may play a role in DNA repair and serve as a proofreading function for DNA polymerase. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, Cree encephalitis, and other diseases of the immune system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]

TREX1 links:

ATRIP (HGNC:33499): (ATR interacting protein) This gene encodes an essential component of the DNA damage checkpoint. The encoded protein binds to single-stranded DNA coated with replication protein A. The protein also interacts with the ataxia telangiectasia and Rad3 related protein kinase, resulting in its accumulation at intranuclear foci induced by DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

ATRIP links:

ATRIP-TREX1 (HGNC:):

ATRIP-TREX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 3-48466945-G-A is Pathogenic according to our data. Variant chr3-48466945-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.39235663). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREX1	NM_033629.6 link	c.290G>A	p.Arg97His	missense_variant	Exon 2 of 2	ENST00000625293.3	NP_338599.1	Q9NSU2-3
ATRIP	NM_130384.3 link	c.*1391G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000320211.10	NP_569055.1	Q8WXE1-1A0A024R2U4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3 link	c.290G>A	p.Arg97His	missense_variant	Exon 2 of 2	6	NM_033629.6	ENSP00000486676.2		Q9NSU2-3
ATRIP	ENST00000320211.10 link	c.*1391G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_130384.3	ENSP00000323099.3		Q8WXE1-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

249418

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135034

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1459402

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726164

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 1

Pathogenic:3

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Jun 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TREX1 c.290G>A (p.Arg97His) results in a non-conservative amino acid change located in the Exonuclease domain (IPR013520) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249418 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TREX1 causing Aicardi Goutieres Syndrome 1, allowing no conclusion about variant significance. c.290G>A has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Aicardi Goutieres Syndrome 1 (e.g. Ellyard_2014, Olivieri_2013, van der Ven_2021, Kuang_2022). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence, demonstrating decreased enzyme activity in an in vitro expression system and lymphocyte function changes in patient derived cells (Olivieri_2013, Pulliero_2012). The following publications have been ascertained in the context of this evaluation (PMID: 31589614, 25138095, 23918923, 22367235, 34490615, 35803721). ClinVar contains an entry for this variant (Variation ID: 225498). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 20, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with TREX1-related conditions. Loss of function is generally associated with recessive disease, while dominant negative variants are associated with dominant disease (OMIM, PMID: 21937424). However, loss of function is the mechanism of disease associated with heterozygous C-terminal frameshift variants identified in individuals with retinal vasculopathy with cerebral leukodystrophy (OMIM). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Aicardi-Goutieres syndrome is predominantly a recessive condition; however, there have been rare cases of a dominant form of the disease reported (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (16 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, two alternative changes with higher Grantham scores, p.(Arg97Ser) and p.(Arg97Cys), have been reported once each as a VUS (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS and as likely pathogenic and pathogenic, with limited clinical information provided (ClinVar, LOVD). However, it has also been observed in two compound heterozygous individuals with Aicardi-Goutières syndrome (PMID: 35803721, PMID: 31130681), a homozygous individual with cerebral systemic lupus erthematosus (PMID: 25138095) and another homozygous individual with severe global developmental delay, leukodystrophy and cerebellar hypoplasia (PMID: 31056085). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated a 20-fold reduction in exonuclease activity compared to wildtype cells (PMID: 25138095). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:1Uncertain:1

Oct 26, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Systemic lupus erythematosus;C0024145:Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Pathogenic:1

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Pathogenic:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 97 of the TREX1 protein (p.Arg97His). This variant is present in population databases (rs200773268, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Aicardi-Goutieres syndrome and/or systemic lupus erythematosus (PMID: 3580372, 23918923, 25138095, 31130681, 34490615, 35803721). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225498). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TREX1 function (PMID: 22367235, 25138095). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.39

T;T

MetaSVM

Uncertain

0.55

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

.;N

REVEL

Uncertain

0.59

Sift

Benign

0.072

.;T

Sift4G

Uncertain

0.0070

.;D

Vest4

0.68

MVP

0.93

ClinPred

0.68

GERP RS

5.0

Varity_R

0.080

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over